Katrina A. Badiola, School of Chemistry, The University of Sydney, NSW 2006, Australia
Murray N. Robertson, School of Chemistry, The University of Sydney, NSW 2006, Australia
Matthew H. Todd, School of Chemistry, The University of Sydney, NSW 2006, Australia
Michael Woelfle, School of Chemistry, The University of Sydney, NSW 2006, Australia (Current address...)

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Abstract

The Pictet-Spengler (PS) reaction has potential for the enantioselective synthesis of praziquantel (PZQ), the drug used worldwide for the treatment of the neglected tropical disease schistosomiasis. Following the recent identification of routes to enantiopure PZQ by classical resolution[Todd, PLoS 2011, Todd, Nature Chemistry 2011] we report here the progress to date on the synthesis of PZQ using the PS reaction. The approach employs a known peptide acetal precursor in an chiral Lewis acid (CLA) -catalyzed cyclization.

Scheme: The general reaction scheme for the enantioselective Pictet-Spengler reaction to PZQ using chiral Lewis acid (CLA) catalysis.

Introduction

The anthelmintic drug praziquantel (PZQ, 1a, Scheme 1) is widely used in the treatment of schistosomiasis and remains the only viable drug for the mass treatment of this disease.[Doenhoff, Curr Opin Infect Dis 2008] PZQ is synthesized and administered as a racemate, even though the inactive (S)-enantiomer is associated with side effects and is responsible for the bitter taste of the pill.[Miculka, PLoS, 2009] Administration of the pure active enantiomer is listed as a priority in the WHO business plan 2008-2013.[WHO Business Plan 2008-2013] Production of PZQ as a single enantiomer while keeping the price approximately as low as the racemate is a challenge - preparation of single enantiomers is more expensive than preparation of racemates, unless relevant stereochemistry is contained within available natural products, which is not the case for PZQ.

Efficient approaches to enantiopure PZQ via resolution of a synthetic precursor were recently developed, both by a collaborative open science community and a contract research organisation.[Todd, PLoS 2011] Resolution approaches are viable candidates for the large-scale preparation of PZQ on economic grounds. Yet there remain potentially very efficient approaches based on asymmetric catalysis that would have the advantage of not requiring either disposal or separation/recycling of the inactive enantiomer. The challenge is twofold: firstly to demonstrate a path to (R)-PZQ using asymmetric catalysis, and then to optimize the process to ensure the catalyst loading does not make such a route prohibitively expensive.

Besides an alternative separation of enantiomers based on chromatography,[Lui, J Pharm Sci, 20034] there has been a single report each of diastereo-[Zhang, J.Chem.Res., Synop 2004] and enantioselective[Czarnocki, Tet Asym 2006] syntheses of PZQ. These routes are not, however, realistic for the large-scale syntheses of PZQ, partly because they use synthetic routes that are not currently used for the large-scale synthesis of the racemate - de novo process optimization for these approaches is not likely to happen given the low profit margin associated with drugs for neglected tropical diseases.

A better approach is to take existing routes to the racemic drug, and make a key step asymmetric. PZQ was originally synthesized by a Reissert process,[Lobich, Cell Mol Life Science 1977] and it is likely that this process is currently used in at least one commercial-scale synthesis of PZQ. This route has the disadvantage of requiring a large amount of cyanide.[Shen Water Res, 2005] There are literature reports of catalytic, asymmetric Reissert processes,[Shibasaki JACS 2001, Guingant, Tet Let, 2005] but surprisingly there are no reports of this reaction being successfully applied to the system required for PZQ - isoquinoline. While the exact routes used to synthesize PZQ on a ton scale are not currently clear, it is likely that one of the main generics suppliers, Shin Poong, employs (or until recently employed) a published method that uses a Pictet-Spengler (PS) cyclization. [Kim, Tet, 1998] The key precursor to this cyclization, and hence the substrate for an asymmetric version of this reaction, is thus likely available in quantity, and can in any case be prepared by a recently-developed and more efficient route than that originally published.[Domling Chem.Eur.J. 2010] A large-scale route to (R)-PZQ is hence a viable possibility via a Pictet-Spengler sequence if a catalyst could be found to effect the required cyclization.

Unfortunately the key cyclization is beyond the current state of the art. There is a small number of reports in the literature of catalytic, asymmetric Pictet-Spengler reactions.[List, JACS, 2006, Hiemstra, Angew. Chem. Int. Ed, 2007] In all cases the aromatic ring involved in the cyclization is electron rich, usually by virtue of containing one or more methoxy substituents. To the best of our knowledge there are no reports of catalytic, asymmetric Pictet-Spengler reactions involving a simple phenyl ring as the reactive aromatic component. Besides the route described above, other racemic syntheses of PZQ have used the PS reaction.[Domling Chem.Eur.J. 2010]

Besides the substrate (7a) required for the synthesis of PZQ by a PS approach, three other peptide acetal starting materials are worthy of investigation: the benzoyl analog (7c) and the dimethoxy-functionalised analogs of both these structures (7b and 7d). The change from cyclohexanoyl to benzoyl might influence the ease of initial acetal cyclisation to generate an acyliminium ion, and the final product of the reaction, the benzoyl analog of PZQ (1c), may be easier to crystallise/purify. Interestingly this benzoyl analog is more potent as an anthelmintic than PZQ itself, yet is not used as the drug of treatment;[REF] regardless, it is possible to convert the benzoyl PZQ analog fairly easily to PZQ.[Todd, PLoS 2011] The two methoxy analogs are clearly of interest as they are more likely to participate in PS cyclizations. In fact the 6,7-di(MeO) analog of PZQ (7b) is itself biologically active,[Rao 2012] so again, the effective production of this molecule is an attractive possible alternative to enantiopure PZQ if the synthesis of (R)-PZQ itself proves intractable.

Scheme 1. Approaches to the Synthesis of Praziquantel and Close Analogs via a Pictet-Spengler (PS) Reaction, and Traditional vs. Ugi methods for Construction of the PS Cyclization Precursors

Question for consideration: PS reactions challenging on rings with no EDG's, but how important is the amide in the reaction?

Results

1. Preparation of Cyclization Precursors

The peptide acetal precursors 7a-d to the PS reaction could be made using a traditional stepwise approach[Kim, Tet, 1998, Min, Arch. Pharm. Res., 1998] or an Ugi 3-component coupling [Domling Chem.Eur.J. 2010] (Scheme 1). These were then shown to undergo PS reactions in the presence of excess acid, to give PZQ and its three analogs as racemates. Investigations of chiral acids were then undertaken collaboratively in a search for an effective catalyst system for optimization.

1a. Conventional Stepwise Synthesis

1b. Synthesis via Ugi Multicomponent Coupling

1b. i) Synthesis of the isocyanides
Isocyanides MW34-3 and MNR4-2 were prepared via the Ugi formamide route from the corresponding amines following Domlings 2-step procedure.[Ugi, Angew Int, 1972,Domling PCT Int, 2009] Attempts to use a Hoffman type procedure produced the desired product (MW34-1)in one step using chloroform as the source of Cl, but this proved less efficient especially on scale up (MW34-2).

Care should be taken in the handling of the isocyanides as they have a strong odour with an unpleasant metallic taste

Scheme: Formation of isocyanides MW34-4 and MNR4-2.

1b. ii) Ugi: Multicomponent Couplings

The desired Ugi products were then produced using the pre-formed isocyanides (MW34-3 and MNR4-2) and two different carboxylic acids (benzoic and cyclohexane) to give the four cyclization precursors, KAB5-2, MNR8-5, MW51-1, MNR10-2 in excellent yields.

2. Racemic Cyclizations

It has been shown in the literature that cyclisation of the peptide acetal intermediate via the Pictet-Spengler reaction occurs in the presence of very strong Bronsted acids. Previous examples include concentrated sulphuric acid [Kim, Tet, 1998] and methane sulfonic acid (MSA) [Domling Chem.Eur.J. 2010].

Triflic acid (TfOH) was screened as a catalyst for the Pictet-Spengler reaction using the four Ugi products from above. At a catalyst loading of 5 mol %, the desired product for the two electron rich systems (MNR8 and MNR10) was isolated in excellent yields of 91 and 96% respectively. Unfortunately, complete cyclisation was not observed for the other two examples and intermediate enediamide was isolated as the major product. Increasing catalyst loading did not help to push these reactions to completion.

Continuing on, metal triflates were then studied with the potential of employing bisoxazoline ligands (BOX ligands) to generate chiral catalysts.[REF] Copper and silver triflate were investigated with the silver triflate being more extensively screened. Again as for the previous examples, electron rich systems (MNR8 and MNR10) cyclised and the desired products were isolated in 78 and 87% yields with a catalyst loading of 10%. No further attempts at this stage were taken to reduce the catalyst loading any further. Also, as before, increasing the catalyst loading did not help to push KAB5-2 and MW51-1 to completion.

Summary

Results:
Use of catalytic vs stoich achiral acid? Results.
Use of chiral acids. Little reaction. What is the evidence for any hemiaminals? Starting material – lots in unactivated. Messy NMR, so some reaction.

Discussion of range of acidity – what we have tried compared to what not.

Supporting Information

Synthesis/Acquisition of Candidate Catalysts

N,N’-bis-3,5-bis[3,5-bis(trifluoromethyl)phenyl]-thiourea

This achiral version of a 'Jacobsens thiourea-catalyst' is a Bronsted-acid which is used for Screening pretests to evaluate if a reaction works under the choosen conditions without using expensive chiral versions of the catalyst.